delta 4-9alpha-halogeno-3beta, 11beta, 17beta-trihydroxy-11alpha-methyl-androstenes and esters thereof



Efiiifi ii Patented Dec. 12, 1961 ice 3,012,941 -9a-HALOGENO 35,115,175TRIROXY-llalglgTI-IYL-ANDRQSTENES AND ESTERS THERE- Albert Wettstein,Georg Anner, and Ludwig Ehmann, 5 Basel, Switzerland, assiguors to CihaPharmaceutical Products Inc, Summit, NJ. No Drawing. Filed June 23,1959, Ser. No. 822,176

Claims priority, application Switzerland .Fuue 25, 1958 13 Claims. (Cl.167- 74) The present invention provides new, highly androgenichalogeno-androstenes of the formula tin. mp

j CHa in which X stands for a chlorine or fluorine atom, is reduced witha complex light-metal hydride, and the resulting compound, if desired,is converted into a 3-ester thereof.

To carry out the reduction according to the present invention thestarting material is treated with a complex light-metal hydride such,for example, as lithium aluminum hydride, lithium boron hydride, sodiumor potassium boron hydride in the presence of a suitable solvent such asether, dioxane, tetrahydrofuran, an alcohol or an acetic acid ester. TheA -3-hydroXy compounds are isolated in known manner, for example bycrystallization and/or chromatography. In contradistinction to thestarting materials the products of the invention give a characteristicred coloration with concentrated sulfuric acid.

The A 17a methyl 9oz halogeno androstene- 3:11:17-triols thus obtainedcan be esterified in the 3- position by known methods. The acid residuesof these esters are those of saturated or unsaturated aliphatic,cycloaliphatic, aromatic or heterocyclic carboxylic acids, preferably oflower aliphatic, monocyclic cycloaliphatic, aromatic or heterocycliccarboxylic acids, lower monocyclic araliphatic or cycloaliphaticcarboxylic acids, such as, for example, of formic, acetic, propionicacid, of the butyric acids, valeric acids, such as n-valeric acid ortrimethylacetic acid, of the caproic acid such as ,B-trimethylpropionicacid or diethylacetic acid, of oenanthic, caprylic, pelargonic, capric,undecylic acids, for example of undecylenic acid, of the lauric,myristic, palmitic or stearic acids, for example of oleic acid,cyclopropyl-, cyclobutyl-, cyclopentyland cyclohexylcarboxylic acids,cyclopropylmethylcarboxylic acid, cyclobutylmethyhcarboxylic acid,cyclopentylethylcarboxylic acid, cyclohexylethylcarboxylic acid, of thecyclopentyl-, cyclohexyl-, or phenyl-acetic acids or -propionic acids,of benzoic acid, phenoxyalkane acids such as phenoxyacetic acid,para-chloro- 70 phenoxy-acetic acid, 2:4-dichlorophenoxyacetic acid, 4-tertiary butylphenoxyacetic acid, 3-phenoxypropionic acid,4-phenoxy-butytic acid, of furan-Z-carboxylic acid, S-tertiarybutylfuran-Z-carboxylic acid, 5-bromofuran-2- carboxylic acid, ofnicotinic acid, of fl-ketocarboxylic acids, for example of acetoacetic,propionylacetic, butyrylacetic or caprionylacetic acid, of amino acidssuch as diethylaminoacetic acid, aspartic acid and the like. Instead ofresidues of carboxylic acids there may be present those of sulfonicacids, phosphoric, sulfuric or hydrohalic acids.

Special importance attaches to esters that contain a group impartingsolubility in water, such as a hydroxyl, carboxyl or amino group, sincethey may be used for the preparation of aqueous solutions. Thesemiesters obtained in this manner are derived from dicarbcxylic acids,for example from oxalic, succinic, maleic, glutaric, dimethylglutaric,pimelic, acetonedicarboxylic, acetylenedicarboxylic, phthalic,tetrahydrophthalic, hexahydrophthalic, endomethylene-tetrahydrophthalic,endomethylenehexahydrophthalic, endoxy-hexahydrophthalic,endoxytetrahydrophthalic, camphoric, cyclopropanedicarboxylic,cyclobutane-dicarboxylic, diglycolic, ethylenebisglycolic,polyethylene-bisglycolic, thioglycolic, furan-dihydrofuran-,tetrahydro-furan-dicarboxylic acids, quinolinic, cinchomeronic acid, aswell as from the polyethylene-glycol monoalkyl ether semiesters of theafore-mentioned dicarboxylic-acids, or from polybasic inorganic acids,such as sulfuric acid, phosphoric acids and the like.

In the so-obtained semiesters the free acid group of the dicarboxylicacids used or of the polybasic inorganic acids can also be furtheresterified. Thus, for example, by reaction with diazomethane inmethanol-ether the methyl esters of the 3-hemidiglycolates,S-hemisuccinates etc. are obtained.

The esters are prepared from the aforementioned acids or their halides,anhydrides, thiol derivatives or ketenes. Transesterification methodsare likewise suitable. To prepare the water-soluble salts the semiestersare reacted in as such known manner, for example with alkali metalhydroxides or carbonates or bicarbonates, more especially with sodiumbicarbonate, or with an organic base such as ethanolamide,diethanolamine, triethanolamine, dibenzylethylenediamine, ephedrine, orwith a-l-phenyl-2- methylaminopropane. It is a special advantage ofthese semiesters that they yield relatively stable aqueous solutionswith the afore-mentioned organic and inorganic bases.

The starting materials are known.

The present invention further covers mixtures of substances intended tobe used in human or veterinary medicine, containing the afore-mentionedhalogenoandrostene compounds in combination with a solid or liquidpharmaceutical excipient. The mixtures of substances are prepared bymethods known per se, for example with the use of pharmaceutical organicor inorganic excipient suitable for parenteral, enteral or localadministration. For this purpose may be used substances that do notreact with the products of the present process such, for example, aswater, vegetable oils, benzyl alcohols, polyethyleneglycols, gelatine,lactose, starch, magnesium stearate, talc, white petroleum jelly,cholesterol or other pharmaceutical excipients. Preferred preparationsare those intended for parenteral administration, advantageously in theform of solutions, more especially oily or aqueous solutions,furthermore suspensions, emulsions or implants; for enteraladministration there are also used tablets or dragees, and for localadministration also ointments or creams. If desired, the preparationsmay be sterilized or contain auxiliaries such as preservatives,stabilizers, wetting agents or emulsifiers, salts for varying theosmotic pressure, or buffers. The con-tent of active substance in thesepreparations, such as of an ampoule, is preferably 0.1-200 mg. or0.03-60%.

10.0 grams of 9a-fiuoro-1l5-hydroxy-l7a-methyl-testosterone aredissolved in 1300 cc. of methanol and 200 cc. of ethyl acetate. Theclear solution is cooled to 5 C. and 2.5 grams of sodium boron hydrideare tipped in; the hydride dissolves rapidly after having been rotatedseveral times, with a slight evolution of hydrogen. The progress of thereduction is observed by periodically checking the ultra-violetabsorption. About 2 hours after the addition of sodium boron hydride,az5-unsaturated ketone can no longer be detected in the ultravioletspectrum, whereas a simultaneous spot test with silver nitrate stillreveals the presence of some excess sodium boron hydride. The Whole iskept overnight at C., clear reaction solution is treated with 10 cc. ofWater and then with 50 cc. of 0.5 N-acetic acid [pH=6 to 7]. The clearsolution is concentrated in vacuo at 40 to 50 C. to about 100 cc.,treated with another 300 cc. of water, and the Whole is once againevaporated in vacuo to 100 cc. The mixture is diluted with 500 cc. ofwater, and the precipitated reaction product is suctioned off,thoroughly washed with water and dried, to yield 9.4 grams of A-9afiuoro-35:115:175 trihydroxy 17a methyl-androstene melting at 206 to207 C. After having been recrystallized from acetone the reactionproduct melts at 215- 216 C. A 3.05, 6.00-6.05, 6.84

A similar reduction of 9e-chloro 115 hydroxy-17 methyltestosterone withsodium boron hydride yields A 9a-chloro-3 5: 115: 175trihydroxy-17a-methyl-androstene.

Example 2 3.38 grams of A-9a-fluoro-35:115:175-trihydroxy-17amethyl-androstene are dissolved in50' cc. of pyridine, treated with cc. of acetanhydride, and the whole iskept overnight at room temperature. The reaction solution is poured intoice water, and the precipitate is suctioned off, washed with a copiousamount of water and dried. ,Recrystallization from ethyl acetate oracetone yields pure A -9a-fluor0-35: 115: l75-trihydroxy 17a. methylandrostene-3-acetate in a yield of 47%.

Analogous reatcion of A 9afluoro-35:i15:175-trihydroxy-l7a-methyl-androstene with propionic acidanhydride in pyridine gives a 76% yield of A -9a-fluoro-35:115:175-trihydroxy 17 oz methyl androstene-S-propionate.

Example 3 3.5 grams of A-9a-chloro-35:ll5:175-trihydroxy-17amethyl-androstene, 50 cc. ofpyridine and 10 cc. of acetanhydride are mixed and kept overnight atroom temperature. The clear reaction solution is poured into ice, andthe precipitate is suctioned oil, Washed and dried in vacuo at 40 to 60C. Recrystallization from ether-kpetroleum ether gives a 70% yield of A-9a-chloro-35:115:1754trihydroxy-l7a-methyl-androstene-3acetate.

Example 4 3.38 grams of A-9a-fluoro-35:115:l75-trihydroxy-17amethyl-androstene are dissolved in50 cc. of pyridine. In the course of 30 minutes a solution of 2.0 cc. oftrimethylacetyl chloride in 25 cc. of pyridine is run in at 20 to 25 C.The whole is kept overnight at room temperature and then further workedup as described in Example 4. Recrystallization cErom ethyl acetateyields 3.2

and the 4* grams of A -9a-fluoro-3 5: l l 5:175atrihydroxy-l7a-methylandrostene-3-trimethylacetate.

A similar reaction of A 9a chloro35:l15:175-trihydroxy-l7a-methyl-androstene with trimethylacetylchloride in pyridine yields A 9achloro-35:ll5:l75-trihydroxy-l7amethyl-androstene-3trirnethylacetate.

Example 6 3.38 grams of A-9a-iluoro65:115:175-t1i-hydroxy-17amethyl-androstene are heated with2.0 grams of succinic acid anhydride in 50 cc. of pyridine for 30minutes on a boiling water bath under nitrogen. The whole is cooled,poured into dilute ice-cold hydrochloric acid, suctionfiltered, washedwith dilute hydrochloric acid and then with water, dried, andrecrystallized from methanol, to yield d -i a-fiuoro 35:1l5:175trihydroxy-17a-methy1- androstene-3-hemisuccinate.

To prepare the water-soluble sodium salt of A-9afluoro-35:115:175-trihydroxy 17oz methyl-androstene-B- hemisuccinate0.438 gram of A -9w. uoro-35zl15z175- trihydroxy-l7a-methyl-androstene-3hernisuccinate is dissolved in 11 cc. of 0.1 N-sodium bicarbonatesolution. The solution is filtered until it is clear and thenlyophilized by a known method, to yield 0.5 gram of the sodium salt of A-9m-fiuoro 35:1151175 trihydroxy 17a methylandrostene-B-hemisuccinate.

Similar reaction of triethanolamine with A -9wfiHOI'O- 35:1l5z175trihydroxy 17a methyl androstene 3- hemisuccinate yields thetriethanolamine salt of A -9afluoro 35:115:175 trihydroxy 17a methylandrostene-3-hemisuccinate.

Example 7 3.38 grams of A-9a-fluoro-35:115:175-trihydroxy-17amethyl-androstene, 2.3 grams ofdiglycolic acid anhydride and 50 cc. of pyridine are heated for 30minutes at C. under nitrogen. The cooled reaction solution is pouredinto ice water, the whole is extracted with methylene chloride and theextract is Washed with dilute hydrochloric acid and water, dried oversodium sulfate and evaporated. The residue is recrystallized frommethanol to yield A 90: fluoro 35:1151175 trihydroxy 17a methylandrostene-B-hemidiglycolate.

Similar reaction of A 9u-Chl0I'O-3B:1lfiil'Yfi il'lllY-droxy-17a-methy1-androstene with diglycolic acid anhydride yields A 9ozchloro 35:115:175 trihydroxyl7a-methyl-androstene 3-hemidiglycolate.

To prepare the water-soluble sodium salt of A -9afiuoro 35: :175trihydroxy 17a methyl androstene-B-hemidiglycolate, 0.454 gram ofA4-9a-fiuoro 35:1l5z175 trihydroxy 17a methyl audrostene -3-hemidiglycolate is dissolved in 11.0 cc. of 0.1 N-sodium bicarbonatesolution, the solution is filtered until it is clear and thenlyophilized, to yield 0.5 gram of the sodium salt of A -9a-fiuor0-3 5: 115: 17 5-trihydroxy-17 a-methylandrostene-3hernidiglycolate.

Example 8 3.50 grams of A 9a chloro 35: 115: t75-trihydroxy-17a-methyl-androstene, 2.0 grams of succinic acid arr-- hydride and 50cc. of pyridine are heated for 30 minutes. on a boiling water bath undernitrogen. Working up as described in Example 6 yields A-9a-chloro-35:1l5:175- trihydroxy-17a-methyl-androstene-3-hemisuccinate.

To prepare the water-soluble sodium salt of A -9a-- chloro 35:115:175trihydroxy 17a methyl androstene-3hemisuccinate, 0.455 gram of A-9a-chloro- 35:ll5:l75 trihydroxy 17cc methyl androstene 3-hemisuccinate is dissolved in 11.0 cc. of 0.1 N-sodiurn bicarbonatesolution and then lyophilized, to yield 0.5 gram of the sodium salt of A-9o-cl1loro-35:115:175-trihydroxy17a-methyl-androstene-3hemisuccinate.

Example 9 0.338 gram of A fluoro 35:115z175 trihydroxy-17a-methyl-androstene, 2.7 grams of tetrahydrophthalic acid anhydrideand 100 cc. of pyridine are heated for 30 minutes at 100 C. undernitrogen. Working up as described in Example 6 yields A-9u-fluoro-35:115:175-trihydroxy 17a methyl androstene 3 hemitetrahydrophthalate.

To prepare the water-soluble sodium salt of A -9afluoro 35: 115: 175trihydroxy 17oz methyl androstene-3-hemi-tetrahydrophthalate 0.487 gramof A -9ufluoro 35:115z-175 trihydroxy 17a methyl androstene 3 hernitetrahydrophthalate is dissolved in 11.0 cc. of 0.1 N-sodium bicarbonatesolution and lyophilized, to yield 0.5 gram of the sodium salt of A-9wfiuoro- 35:115:-175 trihydroxy 17a methyl androstene-3-hemi-tetrahydrophthalate,

Similar reaction of diethanolamine with A -9a-fluoro- 35:115:175trihydroxy 17a methyl androstene 3- hemi-tetrahydrophthalate yields thedicthanolamine salt of A 9a fluoro 35: 115: 175 trihydroxy 17o:methylandrostene-3-hemi-tetrahydrophthalate.

Example 10 0.35 gram of A 9a chloro 35: 115: 175 t-rihydroxy-17a-methyl-androstene, 2.7 grams of tetrahydrophthalic acid anhydrideand 100 cc. of pyridine are heated for 30 minutes at 100 C. undernitrogen. Working up as described in Example 6 yields A 9oz chloro3521151175- trihydroxy 174x methyl androstene 3 hemitetrahydrophthalate.

To prepare the water-soluble sodium salt of A -9a chloro 35:115:l75trihydroxy 17a methyl androstene 3 hemi tetrahydrophthalate 0.507 gramof A 9o: chloro 35:115: 175 trihydroxy 17cc methylandrostene 3 hemitetrahydrophthalate is dissolved in 11.0 cc. of 0.1 N-sodium bicarbonatesolution and lyophilized, to yield 0.52 gram of sodium salt of A 90:chloro 35: 115: 175 trihydroxy 17a methyl-androstene-3-hemi-tetrahydrophthalate.

Example 11 0.338 gram of A -9ot-fluoro-35:115:175-trihydroxy-17a-methyl-androstene is dissolved in 50 cc. of pyridine and in thecourse of 30 minutes a solution of 2.0 grams of benzoyl chloride in 25cc. of pyridine is run in at 20 to 25 C. The mixture is kept overnightat room tempera ture and then worked up as described in Example 4.Recrystallization from ethyl acetate yields A -9a-fiuoro- 35:1l5:175trihydroxy 170a methyl androstene 3- benzoate.

Similar reaction of A-9a-chloro-35:115:175-trihydroxy-17a-methyl-androstene with benzoylchloride in pyridine yields A 9a chloro 35: 115: 175 trihydroxy-17a-methyl-androstenc-3-benzoate.

Example 12 0.338 gram of A 9oz fluoro 35:115:175trihydroxy-17a-methyl-androstene is dissolved in 20 cc. of pyridine and,after adding 0.3 gram of cyclopropanecarboxylic acid anhydride undernitrogen, heated for 30 minutes on a boiling water bath. After allowingthe whole to stand overnight at room temperature the reaction solutionis concentrated under reduced pressure by means of a film still, theresidue is taken up in chloroform and the solution Washed in successionwith dilute hydrochloric acid, water, dilute sodium carbonate and againwith water, dried over sodium sulfate, filtered and evaporated. Onrecrystallization from ethanol, the residue yields A 9a fluoro35:1l5:175 trihydroxy 17amethyl-androstene-3-cyclopropaneformate.

Similar reaction of A 9oz chloro 35: 115: 175trihydroxy-17a-methyl-androstene with cyclopropane-carboxylic acidanhydride in pyridine yields A -9a-chloro- 35:115:175 trihydroxy 17amethyl androstene 3- cyclopropaneformate.

Example 13' 0.8 gram of liquid sulfur tIioxide is added dropwise undernitrogen to 30 cc. of dry pyridine at -10 to -5 C. In the course of 30minutes a solution of 3.4 grams of A 9a fluoro 35:115z175 trihydroxy17oz methylandrostene in 30 cc. of dry pyridine is run in to thepyridine-sulfur trioxide adduct in pyridine with continuous cooling. Thereaction mixture is first stirred for 1-2 hours at 0 C., thepyridine-sulfur trioXide adduct gradually dissolving, and is thenmaintained for 23 hours at room temperature. The pyridine is thenextensively distilled under reduced pressure by means of a centrifugalfilm still. Until crystallization sets in the residue is repeatedlydigested with dry ether, the crystalline magma covered with dry etherand allowed to stand overnight. The reaction mixture issuction-filtered, the crystallisate dissolved in cc. of methanol and thesolution titrated with 1.0 N-sodium methylate to pH=9. The sodiumsulfate precipitating during titration is separated and the filtrateconcentrated at 40 C. under reduced pressure by means of a centrifugalfilm still, the concentrated solution cooled to -40 to 50 C. andintroduced slowly and with stirring into ether. The resultingcrystalline suspension is filtered with suction after cooling overnight,washed with some ether and dried. There are obtained 34 grams of thewater-soluble sodium salt of A -9afluoro 35:115z175 trihydroxy 17amethyl androstene-3-hemisulfate.

0.5 gram of the sodium salt of A -9ot-fluoro-35 175trihydroxy-17u-methyl-androstene-3-hemisulfate is dissolved in 50 cc. ofmethanol and allowed to flow slowly through a column of Amerlite IR-prepared with dilute hydrochloric acid and methanol. The column isrinsed with methanol until the filtrate is practically no longerabsorbed in the ultraviolet spectrum at 240 m The filtrate isconcentrated at a temperature of 40 C. at the most by the film stillmethod, diluted with ether, A -9u-fluoro-35zll5z -trihydroxy-17u methylandrostene-3-hemisulfate precipitating. After allowing the crystallisateto stand overnight in a refrigerator, it is suction-filtered and dried.There is obtained "0.4 gram of A -9a-fiuoro-35: 115:175-trihydroXy-17amethyl androstene-3-hemisulfate which dissolves to give a clear so1utionin dilute sodium bicarbonate solution.

Analogous reaction of n-9a-chloro-35zll5z175-trihydroxy-l7a-methyl-androstene with pyridinesulfur trioXide adduct yields A-9a-chloro-35:115:175-trihydroXy-17amethyl-androstene-3-hemisulfate andfrom that the watersoluble sodium salt of A-9e-chloro-35:115:175-trihydroxy-17ot-methylandrostene-3-hemisulfate.

Example 14 0.4 gram of A-9a-fluoro-35:115:175-trihydroxy-17amethyl-androstene-3-hemisuccinate isdissolved in 20 cc. of methanol, and a solution of diazomethane in etheris added with cooling by means of ice water until the yellow colourpersists. Glacial acetic acid is added drop- WlSB until the mixture isdecolourized which is then concentrated under reduced pressure untilcrystallization sets in. After being allowed to stand overnight in arefrigerator, the crystallisate is suction-filtered. There is obtained0.2 gram of the methyl ester of A -9a-fiuoro- 35: 115:175-trihydroxy-17ot-methyl-androstene-3-hemisuccinate. From the motherliquor there is obtained a further quantity of the methyl ester afterconcentration.

Analogous reaction of diazomethane with A -9a-fluoro-35:115:175-trihydroxy-17a-methyl-androstene-3 hernidiglycolate yieldsthe methyl ester of A -9u-fluoro- 35: 115: 175-trihydroXy-17ot-methyl-androstene -3- hemidiglycolate, of diazomethane with A-9a-fiuoro-35:1l5:175- trihydroxy-17a methyl androstene 3hemitetrahydrophthalate the methyl ester of A -9a-fiuoro-35:115:175-trihydroxy-17a-methyl-androstene 3 hemi tetrahydrophthalate and ofdiazomethane with A 9u-fluOI0- 3 5: 115:175-trihydroxy-17a-methyl-androstenc-3-hernisul- 7 fate the methyl esterof A*-9a-fluoro-3fl:llfl: H S-triliydroxy-l7ot-methyl-androsteneiv'-hemisulfate. I

Using the same procedure there is obtained from A 9a-chloro-3 B: l 15:l7fi-trihydroXy-17oi-methyl-androstene- 3-hemidiglycolate, -succinate,-tetrahydrophthalate and sulfate by reaction with diazornethane inmethanol-ether the methyl ester of A-9wchloro-3B:115:17fi-trihydroxyflat-methyl androstene 3hemicliglycolate, -succinate, -tetrahydrophthalate and sulfate.

What is claimed is:

2. The A -9Ct-Ch1OIO-3fiI l1B:l7B-trihydroxy-l7a-methylandrostene. I

3. A member selected from the group consisting of the B-hemisuccinate ofA -9a-iluoro-3flfl1fi:l7B-trihydroxy-l7o;-methyl-androstene and itssodium and triet'nanolamine salts. I g g 4. A member selected from thegroup consisting of the 3-hernidiglycolate of A-9u-fluoro-3fl:1l1317fl-trihydroxyl7u-rnethyl-androstene and its sodiumsalt.

5. A member selected from the group consisting of the 3-hemidiglycolateof A -9a-chloro-35: 11B: l7p-trihydroxyl7m-methyl-androstene and itssodium salt.

6. A member selected from the group consisting of the 3-hemisuccinate ofA -9a-chloro-3p:llBal7fi-trihydroxy- 17a-methyl-androstene and itssodium salt.

7. A member selected from the group consisting of the3-hemi-tetrahydrophthalate of A-9a-fiuoro-3l3fllfizl7fitrihydroxy-lh-methyl androstene and its sodiumand diethanolamine salt.

8. A member selected from the group consisting of the3-hemi-tetrahydrophthalate of A -9a-chloro-3/3:1113:175-trihydroxy-l7a-methyl-androstene and its sodium salt.

9. A compound selected from the group consisting of A -9oc-fluoro-3B: 1to: l7 8-trihydroxy-l7a methyl androstene, A -9u-cl1loro-3B: 11,8: 17,B-trihydroxy 17a methylandrostene and their 3-esters.

10. A pharmaceutical composition comprising a compound of claim 9,containing the active ingredient in an amount ranging from 0.03%together with a suitable pharmaceutical carrier.

ll. A pharmaceutical composition as claimed in claim 10, containing theactive ingredient in an amount ranging from 0.0360% together with asuitable pharmaceutical carrier in form of tablets.

12. A pharmaceutical composition as claimed in claim 10, containing theactive ingredient in an amount ranging from 0.03-60% together with asuitable pharmaceutical carrier in form of oil ampoules.

13. A pharmaceutical composition as claimed in claim 10,-containing theactive ingredient in an amount ranging from (MB-60% together wi h asuitable pharmaceutical carrier in form of ampoules containing aqueoussolutions.

References Cited in the file of this patent UNITED STATES PATENTS2,837,517 Herr June 3, 1958 Attest:

UNITED STATES PATENT OFFICE CERTIFICATION OF CORRECTION Patent No.3,012,941 December 12 1961 Albert Wettsvtein et al.

It is hereby certified that error appears in the above numbered patentrequiring correction and that the said Letters Patent should read ascorrected below.

Column l line 22, for "atomfi read atom same column line 35 for "atomis" read atom is. column 3, line 41 for "47%," read 74% column 4 line4L9 for "A49qfluoro" read A -9a==f luorolines 70 and 71 for"tu=ihydroxylTq-" read -trihydroxyl7usame column,

line 74, for '"A =f luor0=-" read A =9Qfluoro- -3 column 5,

line lO for "-3 hemi-" read -3--=hemi=-= same column, lines f 18 and 32for "trihydroxy 17(1" each occurrence, read trihydroxyl7q column 6 line48 for "methylandrostene-";

read methyl-androstene =5 column 7 line 20, for 113175 read llgsl'lfi-Signed and sealed this 11th day of September 1962 (SEAL) DAVID L. LADDCommissioner of Patents ERNEST W. SWIDER Attesting Officer

9. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF $4-9A-FLUORO-3B:11B:17B-TRIHYDROXY-17A - METHYL - ANDROSTENE, $4-9A-CHLORO-3B:11B:17B-TRIHYDROXY - 17A - METHYLANDROSTENE AND THEIR 3-ESTERS.
 10. A PHARMACEUTICAL COMPOSITION COMPRISING A COMPOUND OF CLAIM 9, CONTAINING THE ACTIVE INGREDIENT IN AN AMOUNT RANGING FROM 0.03-60% TOGETHER WITH A SUITABLE PHARMACEUTICAL CARRIER. 